The mechanism by which the terminal complement (C) sequence injures cell membranes is poorly understood. Even less well understood are those characteristics of the erythrocyte (E) membrane which predispose to immune injury. Our studies seek to determine mechanisms of immune injury to E from normal humans and patients with paroxysmal nocturnal hemoglobinuria (PNH), and to high potassium (HP) and low potassium sheep E, particularly emphasizing the membrane attack mechanism of C. As clues to the behavior of the membrane attack mechanism, we will study C5 binding, C8 binding, and ultrastructural lesion formation on E. A key feature of our approach will be our study of the lytic response of E when C5 convertase is presented on surrogate E or zymosan. Another important facet of our proposal will be our studies of the influence of fluid phase C inhibitors on the lysis of PNH and normal human E. The intriguing possibility that PNH E lack a membrane associated C inhibitor known to be present in normal E membranes will be studied. Experimental support for such a hypothesis would provide a new dimension in our understanding of complement injury to cell surfaces.